Inhibitor of anticancer drug side effect

ABSTRACT

An object of the present invention is to provide a novel agent for suppressing side effects of an antitumor agent, which can suppress side effects caused by the use of an antitumor agent, such as hair loss. The present invention provides an agent for suppressing side effects of an antitumor agent which comprises a mixture of cyclic and/or straight chain poly lactic acids having a condensation degree of 3 to 20.

TECHNICAL FIELD

The present invention relates to an agent for suppressing side effectsof an antitumor agent and an agent for inhibiting hair loss. Moreparticularly, the present invention relates to an agent that cansuppress side effects of antitumor agent such as adriamycin, and can beused for a pharmaceutical preparation, food for specified health use,health food and the like capable of inhibiting hair loss.

BACKGROUND ART

Recently, a wide variety of antitumor agents have been developed, andadministration of antitumor agents is a major means for treating a solidtumors. Disadvantageously, many antitumor agents do not specifically andselectively affect tumor cells, but they also affect normal cells andproduce side effects. The effectiveness of antitumor agents is enhancedvia, for example, a multiple-drug therapy or short-term megadoses, andsuch techniques are widely applied in clinical settings. However, theissue of side effects resulting from the increased dosage is also aserious concern.

For example, a variety of antitumor agents are currently used inclinical settings. Examples thereof include: alkylating agents, such asnitrogen mustards and cyclophosphamide; antimetabolites, such as5-fluorouracil and cytosine arabinoside; antibiotics, such as mitomycinand bleomycin; plant alkaloids; cisplatin; and hormone preparations.Side effects thereof, such as myelosuppression, hair loss, vomition,digestive tract disorders, hepatotoxicity, nephrotoxicity,cardiotoxicity, pulmonary toxicity, stomatitis, dermatopathy, orneurotoxicity, affect most of the body.

Hair loss is a side effect the severity of which significantly increasesin proportion to the dosage of an antitumor agent and the intervals ofadministration. Although hair loss does not directly affect a patient'slife and does not inflict physical pain upon a patient, the influencethereof on the patient's psychological condition is significant, and itis a serious problem that causes the quality of life (QOL) of thepatient to deteriorate.

Human body hair grows via differentiation of hair matrix cells in thehair follicles in the body. The hair follicles on the head (the hairorgan on the scalp) have the fastest growth rate and the growth periodthereof is long. Accordingly, it is known that hair on the head has theproperty of growing the longest among all forms of body hair, and thatthe number of the hair follicles in the growth stage is large. Simply,alopecia is clinically classified as follows: male pattern alopecia;alopecia areata; senile alopecia; congenital alopecia; alopeciaaccompanying metabolic disorders such as endocrine abnormalities orsystemic diseases such as malnutrition, shock, or persistenthyperthermia; secondary alopecia that follows diseases such as a varietyof cutaneous symptoms that occur in the head hair; and drug alopecia.The causes thereof range from genetic factors to diseases, and alopeciawould damage the hair follicles (the hair organ on the scalp) on thehead. The mechanism of alopecia caused by antitumor agents has not yetbeen elucidated. Due to the significantly higher biological activity ofthe hair organ on the scalp compared with that of the hair organs atother locations, the hair organ on the scalp is susceptible to antitumoragents as are the bone marrow lymphoid tissue and the mucosal epitheliumof the digestive tract, and the hair matrix cells in the hair folliclesare damaged. Consequently, the growth of the hair matrix cell functionsis interrupted, the hair bulb is deformed, and hair falls out in theform of atrophic hair or trichodystrophy. Alternatively, the hair organrapidly moves to the resting stage and hair falls out.

Alopecia induced by antitumor agents frequently occurs with the use of,for example, anthracycline agents, including adriamycin, endoxan, oretoposide, and the severity of alopecia is high with the use of suchagents. Such phenomena are also observed with the use of nitrosourea,5-fluorouracil, cisplatin, interferon, and the like.

Examples of methods for inhibiting hair loss that is a side effectcaused by an antitumor agent include: a method wherein an antitumoragent is administered in combination with an antagonist that is specificthereto (e.g., a method wherein Co-enzyme Q¹⁰ is used in combination);alteration of the route of administration in order to reduce the amountof the antitumor agent reaching the hair organ on the scalp by avoidingoral or intravenous administration (e.g., intraarterial orintraperitoneal administration); and a technique of blocking the bloodflow to the scalp wherein the blood flow to the scalp is reduced withthe use of tourniquets to thereby inhibit the administered antitumoragent from reaching the hair root. However, none of these techniqueshave provided sufficient effects to date. Concerning the alteration ofthe route of administration, intraarterial administration can be onlyapplied to types of cancer, such as hepatic tumors, involving an obviousartery territory. The technique of blocking the blood flow to the scalpdisadvantageously inflicts a great deal of pain upon a patient. Alsoavailable is a technique of cooling the cranium (the head), whereinalopecia is prevented by maintaining the scalp temperature at 22° C. orlower, but the evaluation of the effects attained thereby has not yetbeen confirmed. There is a report that this technique is absolutelyineffective in the case of oral administration, particularly whenantitumor agent dosage is increased. Due to the necessity of cooling ofthe head for a long period of time, disadvantageously, the movement of apatient is restrained during such time, the patient feels uncomfortabledue to his or her appearance, and a caregiver is required to undertakecumbersome tasks. Given these circumstances, development of an agent forsuppressing side effects of an antitumor agent that can be safely usedin order to improve the QOL of the patient during the continuedadministration of antitumor agents has been awaited.

In previous research, a mixture of cyclic and/or straight chain polylactic acids having a condensation degree of 3 to 20 was reported to beuseful as an anti-malignant tumor agent (JP Patent Publication (Kokai)Nos. 9-227388 A (1997) and 10-130153 A (1998)). However, the effects ofthe mixture of cyclic and/or straight chain poly lactic acids having acondensation degree of 3 to 20 on hair loss induced as a side effect ofan antitumor agent have not yet been reported.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a novel agent forsuppressing side effects of an antitumor agent, which can suppress sideeffects caused by the use of an antitumor agent, such as hair loss. Itis another object of the present invention to provide a novel agent forinhibiting hair loss. It is still another object of the presentinvention to provide food and drink for suppressing side effects of anantitumor agent and for inhibiting hair loss utilizing theaforementioned agent.

In order to attain the above objects, the present inventors have studiedthe effects of a mixture of poly lactic acids on suppression of sideeffects of adriamycin by administering a mixture of cyclic and/orstraight chain poly lactic acids having a condensation degree of 3 to 20in combination with adriamycin to a mouse model of cancer. As a result,the aforementioned mixture of poly lactic acids was found to inhibithair loss caused as a side effect of adriamycin. The present inventionhas been completed based on such findings.

Specifically, the present invention provides an agent for suppressingside effects of an antitumor agent which comprises a mixture of cyclicand/or straight chain poly lactic acids having a condensation degree of3 to 20.

Another aspect of the present invention provides an agent for inhibitinghair loss which comprises a mixture of cyclic and/or straight chain polylactic acids having a condensation degree of 3 to 20.

The agent according to the present invention can be preferably used forinhibiting hair loss caused by the use of antitumor agents.

Preferably, the lactic acid, which is a repeating unit in polylacticacid, is substantially comprised of L-lactic acid.

Preferably, the mixture of cyclic and/or straight chain poly lacticacids having a condensation degree of 3 to 20 is a mixture of polylacticacids that is produced by polymerizing lactide in the presence of thecompound represented by formula (3): Me-N(R¹)(R²) wherein Me representsan alkali metal and R¹ and R² each independently represent an aliphaticgroup or an aromatic group.

Preferably, Me represents lithium, and R¹ and R² each independentlyrepresent an alkyl group having 1 to 6 carbon atoms in the aboveformula. More preferably, Me represents lithium, and R¹ and R² representan isopropyl group in the above formula.

Preferably, the mixture of cyclic and/or straight chain poly lacticacids having a condensation degree of 3 to 20 is a substantially cyclicpolylactic acid mixture.

Another aspect of the present invention provides food and drink forsuppressing the side effects of an antitumor agent or inhibiting hairloss, which comprise the aforementioned agent for suppressing sideeffects of an antitumor agent or agent for inhibiting hair lossaccording to the present invention.

A further aspect of the present invention provides the use of a mixtureof cyclic and/or straight chain poly lactic acids having a condensationdegree of 3 to 20 in the production of the agent for suppressing sideeffects of an antitumor agent, an agent for inhibiting hair loss, andfood and drink comprising the same.

A still further aspect of the present invention provides a method forsuppressing side effects of an antitumor agent and/or inhibiting hairloss, which comprises administering an effective amount of a mixture ofcyclic and/or straight chain poly lactic acids having a condensationdegree of 3 to 20 to a mammal such as a human.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an overall view showing the FABMS spectrum (positive mode) ofthe product obtained in Production Example 1. Range: m/z 10.0000 to1305.5900

FIG. 2 is an overall view showing the FABMS spectrum (negative mode) ofthe product obtained in Production Example 1. Range: m/z 10.0000 to2000.0000

FIG. 3 is an enlarged view showing the FABMS spectrum (negative mode) ofthe product obtained in Production Example 1. Range: m/z 10,000 to501.9260

FIG. 4 is an enlarged view showing the FABMS spectrum (negative mode) ofthe product obtained in Production Example 1. Range: m/z 490.2980 to1003.7700

FIG. 5 is an enlarged view showing the FABMS spectrum (negative mode) ofthe product obtained in Production Example 1. Range: m/z 999.9500 to1504.3400

FIG. 6 is an enlarged view showing the FABMS spectrum (negative mode) ofthe product obtained in Production Example 1. Range: m/z 1484.5300 to2000.0000

FIG. 7 is an overall view showing the NMR spectrum of the productobtained in Production Example 1.

FIG. 8 shows the effects of CPL and adriamycin for suppressinghyperplasia.

FIG. 9 shows the results of comparison of the ranges of hyperplasiadevelopment among groups.

BEST MODES FOR CARRYING OUT THE INVENTION

Hereafter, the embodiments of the present invention and the methods forcarrying them out are described in detail.

The agent for suppressing side effects of an antitumor agent and theagent for inhibiting hair loss according to the present invention (whichmay be hereafter referred to as “the agents of the present invention”)comprise, as an active ingredient, a mixture of cyclic and/or straightchain poly lactic acids having a condensation degree of 3 to 20. Theycan be used, for example, for inhibiting hair loss that is caused as aside effect of an antitumor agent.

The term “side effects of an antitumor agent” used herein refers to allthe unfavorable symptoms generated in the organism due to theadministration of antitumor agents. Examples thereof include hair loss,myelosuppression, vomition, digestive tract disorders, hepatotoxicity,nephrotoxicity, cardiotoxicity, pulmonary toxicity, stomatitis,dermatopathy, and neurotoxicity. The agent for suppressing side effectsof an antitumor agent according to the present invention can be used forinhibiting hair loss, among the aforementioned side effects.

Examples of antitumor agents, the side effects (e.g., hair loss) ofwhich should be suppressed by administration of the mixture of polylactic acids according to the present invention, include antibioticantitumor agents, such as adriamycin, daunorubicin, daunomycin,aclacinomycin A, actinomycin D, mitomycin C, chromomycin A₃, bleomycin,peplomycin, neocarzinostatin, and auromomycin. Examples of otherantitumor agents include: etoposide, which is the plant alkaloidpodophyllin compound; other plant alkaloid antitumor agents, such asvincristine, vinblastine, and vindesin; antimetabolic antitumor agents,such as methotrexate, 5-fluorouracil, 5-fluorodeoxyuridine, tegafur,carmofur, cytosine arabinoside, cyclocytidine, 6-mercaptopurine,6-mercaptopurine riboside, and 6-thioguanine; alkylating antitumoragents, such as nitrogen mustards, cyclophosphamide, nimustine,ranimustine, and carboquone; and other antitumor agents, such asL-asparaginase, cisplatin, estramustine, picibanil, krestin, lenthinan,schizophyllan, levamisole, bestatin, forphenicinol, and hormonepreparations.

In the agent and food and drink of the present invention, a mixture ofcyclic and/or straight chain poly lactic acids having a condensationdegree of 3 to 20 is used as an active ingredient.

The term “a mixture of poly lactic acids” used in the present inventionmeans a mixture wherein cyclic and/or straight chain poly lactic acidshaving a condensation degree of 3 to 20 are present at any ratio. Thatis to say, the term “mixture” does not only mean a mixture of polylactic acids having any condensation degree ranging from 3 to 20, but isalso used as a concept including a mixture of cyclic and straight chainpoly lactic acids. As is described below in the present specification,“a mixture of poly lactic acids” can be obtained by condensing lacticacids by dehydration and then performing purification by a suitablemethod. Although the term “a mixture of poly lactic acids” is used inthe present specification for the sake of convenience, this term alsoincludes a poly lactic acid consisting of a single ingredient such as acyclic poly lactic acid having single condensation degree or a straightchain poly lactic acid having single condensation degree.

The term “condensation degree” is used to mean the number of lactic acidunit that is a repeating unit in poly lactic acids. For example, thecyclic poly lactic acid is assumed to have the following structuralformula wherein n represents condensation degree (n=3 to 20).

When “lactic acid” is simply referred to in the present specification,this lactic acid includes all of L-lactic acid, D-lactic acid or amixture comprising these types of lactic acid at any ratio. Preferablyin the present invention, the lactic acid consists substantially ofL-lactic acid. The term “substantially” is used herein to mean that theratio of L-lactic acid units in a mixture of poly lactic acids (numberof L-lactic acid unit/number of L-lactic acid unit+number of D-lacticacid unit×100) is, for example, 70% or more, preferably 80% or more,more preferably 85% or more, further more preferably 90% or more, andparticularly preferably 95% or more. The ratio of L-lactic acid units ina mixture of poly lactic acids depends on the ratio of L-lactic acid andD-lactic acid that exist in lactic acids used as a starting substance.

The methods for producing a mixture of cyclic and/or straight chain polylactic acids having a condensation degree of 3 to 20 are notparticularly limited, and the mixture of poly lactic acids can beobtained by the production methods described, for example, in JapanesePatent Application Laying-Open (Kokai) Nos. 9-227388 and 10-130153 orJapanese Patent Application No. 11-39894 (All publications cited hereinare incorporated herein by reference in their entirety).

More specifically, for example, a mixture of cyclic and/or straightchain poly lactic acids having a condensation degree of 3 to 20 can beobtained by the following method A.

Method A:

First, lactic acid (preferably, lactic acid substantially consisting ofL-lactic acid) is condensed by dehydration under an inactive atmosphere.Examples of the inactive atmosphere include nitrogen gas and argon gas,and nitrogen gas is preferred.

Dehydration and condensation reaction is carried out at a temperature of110° C. to 210° C., preferably 130° C. to 190° C. under normal pressureto reduced pressure of approximately 1 mmHg, and particularly preferablythe reaction is carried out by stepwise decompression and stepwisetemperature rise. A reaction period can be determined as appropriate.For example, the reaction can be carried out for 1 to 20 hours. Wherestepwise decompression and stepwise temperature rise are applied,reaction is performed by dividing the reaction period into two or morepartial reaction periods, and then determining pressure and temperaturefor each of the reaction periods. Where stepwise decompression isapplied, pressure can be reduced, for example, from a normal pressure to150 mmHg and then to 3 mmHg. Where stepwise temperature rise is applied,temperature can be raised, for example, from 145° C. to 155° C. and thento 185° C. Practically, the reaction can be carried out by using theseconditions in combination, for example, 145° C., normal pressure, 3hours; 145° C., 150 mmHg, 3 hours; 155° C., 3 mmHg, 3 hours; and 185°C., 3 mmHg, 1.5 hours.

Subsequently, ethanol and methanol are added to the reaction mixtureobtained by the dehydration and condensation reaction, and the mixtureis filtered. The obtained filtrate is dried to obtain ethanol- andmethanol-soluble fractions. The term “ethanol- and methanol-solublefractions” is used in the present specification to mean fractionssoluble in a mixed solution of ethanol and methanol. In order to obtainethanol and methanol-soluble fractions, a reaction mixture obtained bydehydration and condensation reaction is mixed with ethanol andmethanol, where the ratio of ethanol and methanol can be determined asappropriate. For example, the ratio is ethanol:methanol=1:9. The order,method and the like for adding ethanol and methanol to a reactionmixture are not limited, and may be selected as appropriate. Forexample, ethanol may be added at first to the reaction mixture obtainedby the dehydration and condensation reaction, and then methanol may beadded thereto.

The thus obtained ethanol- and methanol-soluble fractions are subjectedto reverse phase column chromatography, especially to chromatographywhere an octadecylsilane (ODS) column is used. First, fractions elutedwith 25 to 50 weight % acetonitrile aqueous solution of pH 2 to 3 areremoved, and then fractions eluted with 90 weight % or more acetonitrileaqueous solution of pH 2 to 3, preferably 99 weight % or moreacetonitrile aqueous solution, are collected so as to obtain a mixtureof cyclic and/or straight chain poly lactic acids having a condensationdegree of 3 to 20.

The thus obtained mixture of cyclic and/or straight chain poly lacticacids is neutralized with an alkaline substance such as sodiumhydroxide, and is dried under reduced pressure, and then according tostandard techniques, the mixture can be formulated in a desired form asmentioned below.

Other examples of the methods for producing a mixture of cyclic and/orstraight chain poly lactic acids having a condensation degree of 3 to 20used in the present invention include a method described in JapanesePatent Application No. 11-265715 (hereinafter referred to as method B),or a method described in Japanese Patent Application No. 11-265732(hereinafter referred to as method C) (All publications cited herein areincorporated herein by reference in their entirety). Methods B and Cwill be described specifically below.

Method B:

Method B is a method for producing a cyclic lactic acid oligomer whichcomprises polymerizing lactid in the presence of a lithium compoundrepresented by RYLi [wherein R represents an aliphatic group or aromaticgroup, Y represents oxygen atom or sulfur atom]. In the case ofperforming the polymerization reaction, the ratio of the amounts of thelithium compound (RYLi) is 1-0.1 mol, preferably 0.2-0.3 mol per mol oflactide. The reaction temperature is −100 to 0° C., preferably −78 to−50° C. Reaction is preferably carried out by starting from atemperature of −78 to −50° C. and gradually raising it to roomtemperature. The reaction is preferably carried out in the presence of areaction solvent. As the reaction solvent, there can be used, forexample, a cyclic ether such as tetrahydrofuran, diethylether, anddimethoxyethane. The reaction atmosphere can be an inactive gasatmosphere such as nitrogen gas and argon. The reaction pressure is notlimited, and is preferably a normal pressure.

The composition (that is, the mixing ratio of cyclic lactic acidoligomer and a chain lactic acid oligomer) of the lactic acid oligomerobtained as described above fluctuates depending on the lithium compoundused as a reaction assistant. Where a lithium compound of alkyl alcoholhaving a carbon number of 1 to 3 (ROLi) (wherein R represents an alkylgroup with carbon number 1 to 3) is used as a lithium compound, amixture of a cyclic lactic acid oligomer and a chain oligomer(proportion of the cyclic lactic acid oligomer: 80 to 85 weight %) isobtained. When a lithium compound of alkyl alcohol having a carbonnumber of 4 or more such as t-butyl alcohol, or thiophenol compound isused as a lithium compound, substantially only a cyclic lactic acidoligomer can be selectively obtained.

Method C:

This method comprises: (i) a first heating step which comprises heatinglactic acid under a pressure condition of 350 to 400 mmHg and to atemperature of 120 to 140° C. so as to perform dehydration andcondensation, and distilling off and removing only by-product waterwithout distilling lactid off; (ii) a second heating step forsynthesizing a product condensed by dehydration comprising chain lacticacid oligomers as the main ingredient, which comprises, after completionof the first heating step, heating the reaction product to a temperatureof 150 to 160° C. while reducing the reaction pressure to 15 to 20 mmHgat a decompression rate of 0.5 to 1 mmHg/min, wherein only by-productwater is distilled off and removed while avoiding distillation oflactid; and after the reaction pressure is reduced to 15 to 20 mmHg,maintaining the reaction under the same pressure condition and at areaction temperature of 150 to 160° C.; (iii) a third heating step forsynthesizing cyclic oligomers which comprises, after completion of thesecond heating step, heating under a pressure condition of 0.1 to 3 mmHgand at 150 to 160° C. to cyclize the chain lactic oligomer.

In this method, first, in the first heating step, lactic acid is heatedunder reduced pressure to perform dehydration and compression reaction.In this case the reaction period is 3 to 12 hours, preferably 5 to 6hours. To allow the reaction in the first heating step to proceedsmoothly, by-product water produced by condensation of lactic acids bydehydration is distilled off. At this time, distillation of by-productwater is performed such that lactid, which is the dehydrated condensedproduct of two molecules of lactic acid, is not distilled off. Toachieve such purpose, the reaction pressure is maintained at a reducedpressure, preferably 300 to 500 mmHg, more preferably 350 to 400 mmHg.Under this pressure condition, heating is performed at a temperaturerange of 100 to 140° C., preferably 130 to 140° C. The reaction productproduced by reaction in the first heating step mainly comprises as themain ingredient a dehydrated condensed product of 3 to 23 molecules oflactic acid.

To obtain oligomers having an increased average degree of polymerizationin the second heating step after completion of the above first heatingstep, heating is performed at a temperature higher than the reactiontemperature of the above first heating step, preferably at 145° C. to180° C., more preferably 150° C. to 160° C., while the reaction pressureis reduced to 10 to 50 mmHg, preferably 15 to 20 mmHg, so thatdehydration and condensation reaction is further continued.

As with the reaction in the above first heating step, reaction isperformed under a condition where by-product water, but not lactid, isdistilled off, to allow the reaction to proceed smoothly. The rate atwhich reaction pressure is reduced to a pressure in the above range(decompression rate) is normally required to be maintained within arange of 0.25 to 5 mmHg/min, preferably 0.5 to 1 mmHg/min, in order toavoid distillation of lactid and increase the reaction efficiency. Adecompression rate lower than the above range is not preferred becauseit will increase the time required to reduce pressure to a givenpressure. On the other hand, a decompression rate higher than the aboverange is also not preferred because it will cause lactid to be distilledoff together with by-product water.

After the reaction pressure is reduced to a certain pressure, reactionis further continued at that reaction pressure. The heating time periodin this case is 3 to 12 hours, preferably 5 to 6 hours.

A lactic acid oligomer having an average polymerization degree of 3 to30, preferably 3 to 23 is obtained by the reaction in the above secondheating step. The proportion of cyclic oligomers in the oligomers inthis case is normally about 70 to 80 weight %.

In the third heating step, after completion of the above second heatingstep, a reaction pressure is maintained at 0.25 to 5 mmHg, preferably0.5 to 1 mmHg, and reaction is further continued at a temperature of 145to 180° C., preferably 150 to 160° C. A reaction period is 3 to 12hours, preferably 5 to 6 hours. By-product water produced in this caseis also distilled off. In this case, distillation of lactid ispreferably avoided. However, since the reaction product contains almostno lactid, it is not required to specially lower the decompression rate.

Lactic acid oligomers produced by reaction in the above third heatingstep have an average polymerization degree of 3 to 30, preferably 3 to23, and contain cyclic oligomer in the proportion of 90 weight % ormore, preferably 99 weight % or more.

Method D:

In a preferred embodiment of the present invention, the lactides areallowed to react in the presence of an alkali metal compound representedby the formula (3): Me-N(R¹)(R²). The formula (3): Me-N(R¹)(R²) isexplained below.

In the formula (3), Me represents an alkali metal, and each of R¹ and R²independently represents an aliphatic group or aromatic group.

Examples of the aliphatic group defined in the present specificationinclude a straight chain, branched chain, cyclic, or their combinedform, saturated or unsaturated aliphatic hydrocarbon group containing 1to 12, and preferably 1 to 6 carbon atoms. Specific examples includealkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, t-butyl, octyl and dodecyl, and cycloalkyl groups such ascyclopropyl, cyclobutyl, cyclooctyl and cyclododecyl. The aliphaticgroup may be an unsaturated hydrocarbon group having a double or triplebond.

Examples of the aromatic group defined in the present invention includean aryl group and an arylalkyl group, containing 6 to 30, preferably 6to 20, more preferably 6 to 12, and further more preferably 6 to 10carbon atoms. Examples of the aryl group include phenyl, tolyl andnaphthyl, and examples of the arylalkyl group include benzyl, phenethyland naphthylmethyl.

The aliphatic group and the aromatic group may have one or moresubstituent(s). The type of substituents is not particularly limited,and the examples include a straight chain, branched chain, linear orcyclic alkyl group, a straight chain, branched chain, linear or cyclicalkenyl group, a straight chain, branched chain, linear or cyclicalkynyl group, an aryl group, an acyloxy group, an alkoxycarbonyloxygroup, an aryloxycarbonyloxy group, a carbamoyloxy group, a carbonamidegroup, a sulfonamide group, a carbamoyl group, a sulfamoyl group, analkoxy group, an aryloxy group, an aryloxycarbonyl group, analkoxycarbonyl group, an N-acylsulfamoyl group, an N-sulfamoylcarbamoylgroup, an alkylsulfonyl group, an arylsulfonyl group, analkoxycarbonylamino group, an aryloxycarbonylamino group, an aminogroup, an ammonio group, a cyano group, a nitro group, a carboxyl group,a hydroxyl group, a sulfo group, a mercapto group, an alkylsulfinylgroup, an arylsulfinyl group, an alkylthio group, an arylthio group, anureide group, a heterocyclic group (e.g., a monocyclic or condensed ringcontaining at least one or more nitrogen, oxygen or sulfur atom(s) andconsisting of 3 to 12 ring forming members), a heterocyclic oxy group, aheterocyclic thio group, an acyl group, a sulfamoylamino group, a silylgroup, and a halogen atom. In the above, the carbon number of alkyl,alkenyl, alkynyl and alkoxy is generally 1 to 12, and preferably 1 to 6,and the carbon number of aryl is generally 6 to 20, and preferably 6 to10.

In the formula (3), Me represents an alkali metal. Examples of an alkalimetal include Li, Na and K, and Li is preferred.

Among the compounds represented by the formula (3), the compounds havingasymmetric carbon atoms may be any one of (R) form, (S) form, and(R),(S) form.

A method for obtaining an alkali metal compound represented by theformula (3) is not particularly limited, and a person skilled in the artcan obtain the compound as appropriate. For example, the alkali metalcompound can be obtained by reaction of dialkylamine such asdiisopropylamine with an alkylated alkali metal such as n-butyllithium.More specifically, this reaction can be carried out, for example, bymixing a solution containing dialkylamine in an inert solvent such asTHF with a solution containing an alkylated alkali metal in an inertsolvent such as hexane under conditions that are inactive for thereaction, e.g., under a nitrogen gas atmosphere, and then stirring themixture. The reaction temperature is not particularly limited, as longas the reaction progresses, but it is preferably −78° C. to roomtemperature. The reaction temperature can be set as appropriate.

When lactides are polymerized in the presence of a compound representedby the formula (3), the used amount of the compound represented by theformula (3) (Me-N(R¹)(R²)) is preferably 0.1 to 1 mol, and morepreferably 0.2 to 0.3 mol per mole of lactide.

When the polymerization reaction of lactides is carried out, thereaction temperature is not particularly limited as long as the reactionprogresses, but it is preferably −100° C. to room temperature, and morepreferably −78° C. to room temperature.

Polymerization reaction of lactides is preferably carried out in thepresence of a reaction solvent. The reaction solvent is not particularlylimited as long as it is inactive for the reaction. Examples ofpreferred solvents include cyclic ethers such as tetrahydrofuran,diethylether, and dimethoxyethane. Examples of reaction atmospheres tobe used may include inactive gas atmospheres such as nitrogen gas andargon gas. Reaction pressure is not particularly limited, and it ispreferably normal pressure.

The composition of the mixture of linear and cyclic lactic acidoligomers which is obtained by the method as mentioned above is altereddepending on the type of the compound of the formula (3) used as areaction assistant and the reaction conditions. Preferably, the contentof linear lactic acid oligomer is higher than that of cyclic lactic acidoligomer.

According to the method as mentioned above, there is produced a mixtureof linear and cyclic lactic acid oligomers represented by the followingformula (1) or (2):

wherein m represents an integer of 1 to 18, and n represents an integerof 1 to 18.

The above methods A, B, C and D merely show some of specific examples ofmethods of producing a mixture of poly lactic acids used in the presentinvention. A mixture of poly lactic acids which is produced by othermethods can also be used in the present invention.

When required, the agent of the present invention can be prepared byusing, in addition to the essential component as described above,components or additives used for preparation of a dug such as medicaldrugs, quasi-drugs and the like by free selection and combination in arange which does not damage an effect of the invention. The agent of thepresent invention can be used by compounding it in medical drugs,quasi-drugs and the like in addition to a use as a single drug.

The form of the agent of the present invention is not speciallyrestricted, but the appropriate form most suitable for a purpose can beselected from drug forms for oral administration or parenteraladministration.

The drug preparation form suitable for oral administration includes, forexample, a tablet, capsule, powder, drink, granule, fine granule, syrup,solution, emulsion, suspension, chewable and the like. The drugpreparation form suitable for parenteral administration includes, forexample, injection (subcutaneous injection, intramuscular injection,intravenous injection and the like), external use, drip, inhalation,spray and the like and, however, is not restricted to these forms.

A liquid drug preparation, for example, solution, emulsion or syrup,which is suitable for oral administration, can be prepared by usingwater, saccharides such as sucrose, sorbit and fructose, glycols such aspolyethylene glycol and propylene glycol, oils such as sesame oil, oliveoil and soybean oil, antiseptic agents such as p-hydroxy benzoic acidesters, and flavors such as strawberry flavor and peppermint. On theother hand, solid drug preparation, for example, tablet, capsule,powder, granule and the lice, can be prepared by using an excipient suchas lactose, glucose, sucrose and mannite, a disintegrating agent such asstarch and sodium alginate, a lubricant such as magnesium stearate andtalc, a binder such as polyvinyl alcohol, hydroxy propyl cellulose andgelatin, a surfactant such as fatty acid ester, a plasticizer such asglycerin.

The drug preparation for injection or drip suitable for parenteraladministration includes preferably the material, which is the activeingredient, as described above in a sterilized water-based medium, whichis isotonic to blood of a recipient, in a dissolved or suspendedcondition. For example, in case of the injection, the solution can beprepared by using a water-based medium and the like composed of a saltsolution, a glucose solution, or the mixture of the glucose solutionwith the salt solution. The drug preparation for intestinaladministration can be prepared by using a carrier such as cacao butter,hydrogenated fat or hydrogenated carboxylic acid, and can be used as asuppository. In addition, for preparation of spray, a carrier whichallows the material being the active ingredient as described above todisperse as fine particles, does not irritate a mouth cavity and an airway mucosa of the recipient, and makes absorption of the activeingredient easy, can be used. The carrier is specifically exemplified bylactic acid, glycerine and the like. In accordance with a property ofthe material being the active ingredient and the carrier to be used, thedrug preparation having forms such as an aerosol or dry powder can beprepared. These preparations for parenteral administration are alsoadded with 1 or 2 or more species of eatables and drinkables selectedfrom glycols, oils, flavors, antiseptic agents, excipients,disintegrating agents, lubricants, binders, surfactants, plasticizers orthe like.

The dose and administration frequency of the agent of the presentinvention can be properly selected in accordance with various factorsincluding a purpose of administration, a form of administration,conditions of a recipient such as an age, body weight and sexuality and,however, as a rule, the amount of administration of the activeingredient ranges from 1 to 10,000 mg/kg/day, preferably 10 to 2,000mg/kg/day, more preferably 10 to 200 mg/kg/day. It is preferable toadminister the preparation of the amount as described above in 1 to 4frequencies a day.

The timing of administration of the agent of the present invention isnot particularly limited. When suppression of side effects of anantitumor agent is intended, the agent of the present invention may beadministered before, during, or after the administration of theantitumor agent. Since the agent for inhibiting hair loss according tothe present invention has the effect of inhibiting hair loss, it can beingested not only at the time of administration of the antitumor agentbut also on a routine basis in the form of health foods orpharmaceutical preparations.

The present invention also relates to food and drink for suppressing theside effects of an antitumor agent or inhibiting hair loss, whichcomprises a mixture of cyclic and/or straight chain poly lactic acidshaving a condensation degree of 3 to 20. Namely, the mixture of cyclicand/or straight chain poly lactic acids having a condensation degree of3 to 20 which is used in the present invention can be not only used inthe forms of a single preparation as described above, but also can beused by compounding it in food and drink.

A compounding form of food and drink according to the invention is notspecially restricted, when it is satisfied to compound the mixture ofpoly lactic acids without decomposition.

The product of food and drink according to the present inventionincludes specifically a health food or a supplementary food includingbeverages, which is generally called a refreshing drink, drink agent,health food, specified health food, functional food, function activatingfood, nutriceutical food, supplement, feed, feed additive and the like.

Food and drink include arbitrary food and dinks, and examples thereofinclude confectionaries such as chewing gum, chocolate, candy, tabletconfectionary, jelly, cookie, biscuit and yogurt, cold confectioneriessuch as ice cream and ice confectionary, beverages such as tea,refreshing drink (including juice, coffee, cocoa and the like),nourishment drink agent and esthetic drink agent, bread, ham, soup, jam,spaghetti, frozen foods. Alternatively, the mixture of poly lactic acidsused in the present invention can also be used by adding it to aflavoring material or a food additive. By taking food and drinkaccording to the present invention, the effect of suppressing sideeffects of an antitumor agent is obtained to provide safe food and drinkwhich show no substantially harmful adverse effect.

The food and drink according to the present invention can be obtained bydirectly mixing and dispersing the mixture of poly lactic acids to acommon material used for foods and then processing the same in a desiredform by a publicly known method.

The food and drink according to the present invention encompasses foodand drink in every form, and the types are not specifically limited.That is, the food and drink can be provided by mixing the agent forsuppressing side effects of an antitumor agent according to the presentinvention into the above-mentioned various food and drink, or variousnutrient compositions, such as various oral or enteral nutrientpreparations or drinks. Compositions of such food and drink may includeprotein, lipid, carbohydrate, vitamin and/or mineral, in addition to themixture of cyclic and/or straight chain poly lactic acids having acondensation degree of 3 to 20. The form of the food and drink is notspecifically limited, and may be in any form, such as solid, powdery,liquid, gel, and slurry forms, so far as it is in a form that is easilyingested.

The content of the mixture of poly lactic acids in the food and drink isnot specifically limited, and is generally 0.1 to 20 weight %, morepreferably approximately 0.1 to 10 weight %.

The mixture of poly lactic acids is preferably contained in the food anddrink in an amount which achieves an effect of suppressing side effectsof an antitumor agent or inhibiting hair loss which is an object of thepresent invention. Preferably, about 0.1 g to 10 g, more preferablyabout 0.5 g to 3 g, of the mixture of poly lactic acids is contained perfood or drink to be ingested.

The present invention is further described in the following examples,but the scope of the present invention is not limited by the examples inany way.

EXAMPLE Production Example 1 Production of a Mixture of Poly LacticAcids (Hereinafter Referred to as CPL)

The reaction scheme of Production Example 1 is shown below.

0.63 ml of n-butyllithium (1.6 M hexane solution, 1 mmol) was added to a5 ml THF solution containing 0.101 g (1 mmol) of diisopropylamine at 0°C. under a nitrogen gas atmosphere, and the obtained mixture was stirredfor 10 minutes, so as to obtain lithium diisopropylamide (LDA).Thereafter, 4 ml of THF solution containing 0.577 g (4 mmol) ofL-(−)-lactide was added thereto followed by stirring for 15 minutes forreaction. Thereafter, 20 ml of a saturated ammonium chloride aqueoussolution was added to the obtained reaction mixture to treat thereaction, and 10 ml of water was further added thereto. Extractions werecarried out 5 times with THF (50 ml), and the organic layer was driedwith anhydrous sodium sulfate. After anhydrous sodium sulfate wasfiltrated, the organic solvent was subjected to vacuum concentration, soas to obtain 0.53 g of a crude product. 6 ml of ether was added to theobtained crude product, and the mixture was immersed in an ultrasoniccleaner for 10 minutes for filtration, so as to obtain 0.39 g of a whitesolid product having a melting point of 125° C. to 129° C.

The physical data of the obtained product are shown in FIGS. 1 to 7.From the FABMS and NMR data shown in FIGS. 1 to 7, it was confirmed thata 3-mer to 21-mer cyclic lactic acid oligomer and a 3-mer to 27-merlinear lactic acid oligomer were present in the solid product.

Test Example 1

(Material and Method)

Male mouse models (CBA/J) of spontaneous alveolar epithelial hyperplasiawere employed as test animals. These mice develop alveolar epithelialhyperplasia 12 to 15 weeks after birth. Accordingly, they were raisedwith normal feeds until 19 weeks after birth. They were then dividedinto: the group to which feeds containing 0.01% CPL (prepared inProduction Example 1) was administered; the group to which adriamycin(ADM) was administered; the group to which feeds containing 0.01% CPLand adriamycin were administered; and the group that did not experienceadministration. CPL was mixed with powder feeds (CE-2). The daily dosageof adriamycin (ADM) was 0.1 mg/kg per mouse, and administration was madeintraperitoneally once a day for three consecutive days, followed bydrug withdrawal for 11 days. This procedure was designated asconstituting a single course, and eight courses thereof were conducted.

At the time of ADM administration, the body weights of mice weremeasured and their general conditions were observed. In particular, theoccurrence of hair loss was carefully observed. The mice were subjectedto autopsy 36 weeks or 37 weeks after birth (with an administrationduration of 17 weeks or 18 weeks), and samples were recovered. Tissueblocks were obtained from 3 sites each of the extirpated right and leftlungs (6 sites in total), the recovered tissue fragments were fixed,fragments embedded in hydrophilic methacrylate resins were subjected toH-E staining, and the ranges of alveolar epithelial hyperplasia werecompared.

(Results)

(1) Change in Body Weight

Body weights of all individuals were measured every other week, and nosignificant differences were observed among groups.

(2) Effects of Alleviating Side Effects

Hair loss was observed around the eyeballs and the skin of the upperlips of 90% of individuals (9 out of 10 cases) in the group to which ADMalone had been administered. Such hair loss was not observed in anyindividual in the group to which CPL alone had been administered or thegroup to which ADM and CPL had been administered in combination. Thisindicates that CPL had the effects of suppressing side effects caused byADM (Table 1). TABLE 1 Comparison of side effects (hair loss)development Number of indi- viduals under- Number of indi- going hairloss viduals under- around the going hair loss eyeballs at the upper lipGroup to which CPL had been 0 0 administered (n = 7) Group to which CPLand ADM 0 0 had been administered (n = 8) Group to which ADM had 9 9been administered (n = 10) Group that did not experience 0 0administration (n = 10)(3) Effects of Inhibiting Hyperplasia

Tissue sections of the tissue samples of the right and left lungsextirpated from the individuals (from 3 sites each, 6 sites in total)were prepared, the range of hyperplasia in the sections was classifiedinto five levels, and groups were compared with each other. The resultsare shown in FIG. 8. As is apparent from the results shown in FIG. 8,the sections with rates of hyperplasia development of less than 10%accounted for 69.1% of the whole in the group to which CPL had beenadministered. This was approximately 8.3 times as high as that (8.3%) ofthe group to which ADM had been administered. Similarly, such sectionsaccounted for 47.8% of the group to which combined administration hadbeen made (the group to which CPL and ADM had been administered). Thisratio was approximately 5.8 times as high as that of the group to whichADM alone had been administered.

The above results indicate that the effect of CPL for inhibitinghyperplasia was superior to that of AMD and that the combinedadministration also enhanced the effect of ADM.

The range of hyperplasia development in each individual was compared.This comparison revealed that the number of individuals with a range ofdevelopment of less than 30% was 5 out of 7 individuals (71.4%) in thegroup to which CPL had been administered, and that of the group to whichcombined administration had been made (the group to which CPL and ADMhad been administered) was 3 out of 8 individuals (37.5%). In the caseof the group to which ADM had been administered, sections with rates ofhyperplasia development of 50% or more were observed in all individuals,as was the case for the group that did not experience administration(FIG. 9).

(Conclusions)

The antitumor effect of CPL was compared with that of ADM, employing theeffect of inhibiting alveolar epithelial hyperplasia as an indicator. Asa result, the effect of CPL to inhibit hyperplasia was found to behigher than that of ADM under the administration conditions of thisexample.

Hair loss was observed in 90% of the individuals in the group to whichADM had been administered, which indicates that side effects of ADM haddeveloped. In contrast, hair loss was not observed in any individual ofthe group to which CPL had been administered, and no abnormality thatcould be a side effect was observed in terms of appearance.

CPL was administered to the test group to which ADM had beenadministered, and the effects thereof were examined. As a result, CPLwas found to enhance the effects of ADM to inhibit tumors and to inhibithair loss that had occurred in the group to which ADM had beenadministered.

Test Example 2

When several mice are raised in the same cage, examples of possiblestressors include overcrowded conditions and a case where a dominantmale is present in the group. Under such conditions, hair loss andwhisker loss are known to occur. In order to inspect the influence ofthe overcrowded conditions, 13 groups each consisting of 5 individuals(the group to be raised under normal conditions) and 3 groups eachconsisting of 10 individuals (the group to be raised under overcrowdedconditions) (the number of individuals is 2 times of that of the normalcondition) were prepared, and those groups were independently raised inthe cages of the same size (depth: 41.5 cm; width: 26 cm; height: 24.5cm).

Under overcrowded conditions, hair loss and whisker loss were observedin all individuals in 2 out of 3 cages, and hair loss and whisker losswere observed in 9 out of 10 individuals in 1 out of 3 cages. In thecase of the groups that had been raised under normal conditions, hairloss and whisker loss were observed in 4 out of 5 individuals in 3 outof 13 cages, no change was observed in 9 out of 13 cages, and hair lossand whisker loss were observed in 1 out of 5 individuals in 1 out of 13cages (Table 2). TABLE 2 Occurrence of hair loss and whisker loss in agroup that had been raised under overcrowded conditions and in a groupthat had been raised under normal conditions Hair loss and whisker lossdevelopment All Excluding 1 Only 1 individuals mouse mouse none Groupthat had been 2 1 0 0 raised under overcrowded conditions (3 cages)Group that had been 0 3 1 9 raised under normal conditions (13 cages)

Test Example 3

Subsequently, mice that did not develop hair loss or whisker loss in thegroup that had been raised under normal conditions were identified. Thismouse was removed from a cage containing only one such mouse and it wastransferred to the cage in which hair loss or whisker loss had not beenobserved in all individual in a group that had been raised under normalconditions. As a result, individuals in the cage to which theaforementioned mouse had been transferred developed hair loss andwhisker loss. In contrast, hair growth and whisker growth were observedin individuals in the-cage where the aforementioned mouse had originallyresided. Based on this phenomenon, when only 1 mouse did not develophair loss or whisker loss in a cage, this individual was designated asthe dominant male.

Test Example 4

Based on the results attained in Test Examples 2 and 3, hair loss andwhisker loss were observed under overcrowded conditions or in thepresence of a dominant male. Even when the number of individuals to beraised in the same cage was reduced, hair loss or whisker loss was foundto occur in the presence of the dominant male. Accordingly, only thecage in which the dominant male was not present among the group that hadbeen raised under normal conditions was selected, and the effects of CPLfor alleviating side effects of an antitumor agent were examined.

(1) Method

Mouse models of spontaneous cancer (CBA/J, 5 males) were raised in acage until the 54th week, and it was confirmed that hair loss, whiskerloss or the like did not occur. Thereafter, they were divided into: thegroup to which an antitumor agent (adriamycin, ADM) had beenadministered; the group to which CPL-containing feeds had beenadministered; and the group to which ADM had been administered incombination with CPL, and these groups of mice were raised. The dailydosage of ADM was 0.2 mg/kg per mouse, and administration was madeintraperitoneally once a day for 3 consecutive days, followed by drugwithdrawal for 11 days. This procedure was designated as constituting asingle course and then continued. CPL was mixed with feeds (CE-2) inamounts of 0.01% thereof.

(2) Results

After the initiation of the experiment, whisker loss and hair loss atthe upper jaw were observed on the 6th week (at the third course) in thegroup to which ADM had been administered (Table 3), and they werecontinuously raised until the 18th week. It was found that hair loss andwhisker loss did not occur in the group to which combined administrationhad been made and in the group to which CPL had been administered.Accordingly, CPL was found to have the effect of inhibiting side effectsof an antitumor agent. TABLE 3 Side effect development in each groupHair loss and whisker loss (number of individuals) Group to which ADMhad been 4 administered (n = 10) Group to which ADM and CPL had been 0administered (n = 9) Group to which CPL had been 0 administered (n = 10)Group that did not experience 0 administration (n = 10)

INDUSTRIAL APPLICABILITY

The agent for suppressing side effects of an antitumor agent and theagent for inhibiting hair loss according to the present invention can beused for inhibiting side effects such as hair loss caused by theadministration of antitumor agents. The agent for suppressing sideeffects of an antitumor agent according to the present invention canenhance the antitumor effect of antitumor agents. Further, since amixture of poly lactic acids that is used as an active ingredient in thepresent invention is a less-condensed form of lactic acid derived from abiological component, the mixture of poly lactic acids has highbiocompatibility and few side effects.

1. An agent for suppressing side effects of an antitumor agent whichcomprises a mixture of cyclic and/or straight chain poly lactic acidshaving a condensation degree of 3 to
 20. 2. An agent for inhibiting hairloss which comprises a mixture of cyclic and/or straight chain polylactic acids having a condensation degree of 3 to
 20. 3. The agentaccording to claim 1 which is used for inhibiting hair loss caused bythe use of antitumor agents.
 4. The agent according to claim 1 whereinthe lactic acid, which is a repeating unit in polylactic acid, issubstantially comprised of L-lactic acid.
 5. The agent according toclaim 1 wherein the mixture of cyclic and/or straight chain poly lacticacids having a condensation degree of 3 to 20 is a mixture of polylacticacids that is produced by polymerizing lactide in the presence of thecompound represented by formula (3): Me-N(R¹)(R²) wherein Me representsan alkali metal and R¹ and R² each independently represent an aliphaticgroup or an aromatic group.
 6. The agent according to claim 5 wherein Merepresents lithium.
 7. The agent according to claim 5 wherein R¹ and R²each independently represent an alkyl group having 1 to 6 carbon atoms.8. The agent according to claim 5 wherein Me represents lithium, and R¹and R² represent an isopropyl group.
 9. The agent according to claim 1wherein the mixture of cyclic and/or straight chain poly lactic acidshaving a condensation degree of 3 to 20 is a substantially cyclic polylactic acid mixture.
 10. Food and drink for suppressing the side effectsof an antitumor agent or inhibiting hair loss, which comprises the agentaccording to claim 1.